Chemists use newt toxin to ‘see’ pain in a living animal

Newts and many other animals are poisonous because the toxins they contain bind to channels on the surface of nerves and prevent those nerves from firing. If chemists could create a version of the toxin that only latched onto the channels in nerves that signal pain, the chemical could conceivably block pain neurons—therefore blocking the sensation of pain—without interfering with other nerves like the ones that signal muscles to move. (Credit: "California newt" via Shutterstock)

By studying newts, scientists have found a way to tag and take images of the location where pain is generated in living rats.

The work began in the 1960s, when Stanford University scientists discovered that the native newts had a chemical in their skin and eggs identical to the potent toxin found in pufferfish. The newts are only toxic if eaten.

The late chemist Harry Mosher spent much of his career analyzing and attempting to synthesize this toxin and related molecules, collectively called guanidinium toxins. They turned out to be an interesting group of molecules for chemists who like to develop new ways of stitching atoms together to form molecules.

One such chemist, Justin Du Bois, a professor at Stanford, started a lab focused on making and modifying the structures of the guanidinium toxins.

Block pain neurons

Du Bois didn’t initially know about Mosher’s early work, but when he did they had a conversation that sent Du Bois in a new direction. In nature, pufferfish, frogs, and many other animals are poisonous because the toxins they contain bind to channels on the surface of nerves and prevent those nerves from firing.

Mosher pointed out that if someone could create a version of the toxin that only latched onto the channels in nerves that signal pain, the chemical could conceivably block pain neurons—therefore blocking the sensation of pain—without interfering with other nerves like the ones that signal muscles to move.

“He was the one who first said to me that if there was some way of localizing the site of action of the drug it would make for a great pain medicine,” Du Bois says. “I thought if we can make and modify it and make it stay at the site of the injection we would really have something.”

Better picture of pain

Meanwhile, across the street from where Du Bois and his students were getting ever better at synthesizing guanidinium toxin variants, a new radiologist on campus, Sandip Biswal, was growing frustrated with his inability to diagnose the cause of pain.

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Biswal, an associate professor of radiology at the Stanford University Medical Center, spent a lot of time imaging parts of the body where people said they felt pain, trying to find the source. It was a frustrating task because often the source of pain isn’t obvious, and sometimes the source is far removed from where a person feels the sensation of pain.

Other times, he’d see something that looked painful, surgeons would fix it, and the patient would still be in pain.

“All this made me think that we needed to be able to image pain more accurately,” Biswal says. “It would be great if we could take a picture of something that is actively sending pain signals up to the brain.”

Biswal and Du Bois met, realized their overlapping interests, and obtained funding to work together. Their initial goal was to modify guanidinium toxins to bind neurons signaling pain and give off a signal visible outside the body, work they published recently in the Journal of the American Chemical Society.

Du Bois worked with Frederick Chin, an assistant professor of radiology, to create a modified version of guanidinium toxins that contained a non-toxic molecular tag commonly used for imaging chemicals in the body. With this molecular flag, scientists would be able to trace the location of this modified toxin in an animal.

Success in rats

The group tested the new compound in rats that had leg injuries. After injecting the compound into these animals, they could see it located in the leg that had a nerve injury but not in the opposite, uninjured leg. The chemical had latched onto those nerves signaling pain.

Du Bois says that although the results show potential for human applications, much needs to be done to translate work from rodents to humans.

The group has formed a company to refine the compound so it binds even more specifically to neurons conducting pain and to ensure that it will be safe to test in people. The group members hope the work will one day help doctors locate the source of a patient’s pain and also perhaps produce a new class of drug for treating pain.